tbuckley/cabot-search huggingface dataset:
Abstract 14778: Combined Shear Stress-Molecular Imaging for the Evaluation of Early Arterial Healing Responses Following Implantation of Bioresorbable Scaffold With Different Strut Thickness
Authors: Sunwon Kim, Hyun-Sang Park, Joon Woo Song, Jae Won Ahn, Hongki Yoo, Wang-Yuhl Oh, Kyeongsoon Park, Jin W Kim
Journal: Circulation (2022)

Introduction and Hypothesis: Arterial healing following stent implantation involves a series of biological reactions such as thrombosis, inflammation, neointimal regeneration. Clinical evidences have shown favorable arterial healing after thin-strut stents, however, there has been a lack of in vivo imaging evidence on how strut thickness affect vascular healing process. We evaluated local endothelial shear stress (ESS) and healing response of a thin-strut bioresorbable scaffold (BRS, 100μm) compared to first-generation 157μm-thickness ABSORB. Methods and Results: BRS and ABSORB were simultaneously implanted in left coronary arteries of the same pigs (n=7). Detailed scaffolded-artery 3D model was reconstructed based on OCT and angiography. Scaffold-related inflammation response was serially assessed by dual-modal OCT-near-infrared fluorescence (OCT-NIRF) molecular imaging using macrophage-mannose receptor-Cy7 as an inflammation-targeting agent. On ESS analysis, regions with athero-prone low ESS were significantly greater in thick-ABSORB compared to BRS. Dual-modal OCT-NIRF imaging visualized arterial inflammation activity at peri-strut regions in vivo (Figure). Based on coregistered ESS-NIRF data, we found a significant inverse correlation was found between ESS and NIRF activity (p&lt;0.0001), suggesting immune-modulating effect of ESS during early stent healing phase. Arterial inflammation, quantified as target-to-background ratio, was significantly lower in thin-strut BRS than ABSORB at 2 weeks (p&lt;0.01). At week 3, unlike ABSORB with residual peri-strut NIRF signals, inflammation activity dissipated significantly in BRS. Ex vivo confocal fluorescence microscopy (Figure) and immunohistochemical analysis well corroborated the findings in vivo . Conclusions: Thin-strut BRS was associated with less inflammation and rapid resolution of inflammation compared to thicker-strut ABSORB. This study provides in vivo imaging insights into how strut thickness affects early arterial healing and the importance of ESS as an inflammatory modulator. Our comprehensive imaging strategy enabling evaluation of complex interplay between scaffold, ESS, and artery is expected to enhance understanding of stent healing.
Abstract 13604: Sodium-Glucose-Cotransporter-2 Inhibitor (SGLT2i) Exposure in the Immediate Post-Acute Kidney Injury Period in Patients Hospitalized With Acute Heart Failure is Associated With Improved Outcomes
Authors: Sanchit Kumar, Abinet Aklilu, Tariq Ahmad, F. Perry Wilson
Journal: Circulation (2022)

Introduction: Sodium-Glucose Cotransporter-2 inhibitor (SGLT2i) use during or immediately following Acute Heart Failure (AHF) exacerbation has shown clinical benefit including improved symptoms, lower frequencies of re-hospitalization for heart failure and death. However, effects of SGLT2i use immediately following acute kidney injury (AKI) on mortality and renal recovery in this setting are unknown. Hypothesis: Among patients admitted with AHF who sustain in-hospital AKI, exposure to SGLT2i in the immediate post-AKI period would be associated with better outcomes. Methods: Adult patients admitted across 5 hospitals between January, 2020 and April, 2022 with acute heart failure (NT-pro-BNP &gt;500ng/L and receipt of IV diuretic within 24 hours of admission) and KDIGO-defined AKI during hospitalization were included. Advanced CKD (eGFR ≤15 ml/min/1.72m2) and those prescribed SGLT2i &gt; 10 days after AKI were excluded. AKI recovery and death were compared between the exposed and unexposed cohorts using a time-varying Cox-regression analysis after adjusting for potential confounders. Results: In this retrospective cohort of 3599 individuals admitted with AHF that developed AKI during hospitalization, 293 patients received SGLT2i within the 10 days post-AKI. The median (IQR) time to AKI after admission was 24 (1.41-64.48) hours. 36.52% of the SGLT2i exposed had renal recovery pre-SGLT2i exposure. For the SGLT2i-exposed (pre-renal recovery) vs. unexposed groups, rates of 14-day renal recovery were not significantly different (adj. HR 0.99, 95% CI 0.82-1.19, p=0.90). However, the post-AKI SGLT2i-exposed group had a lower risk of death at 30 days (adj. HR 0.39, 95% CI 0.19-0.79, p=0.009) after adjustment for potential confounders. Conclusion: In a retrospective cohort of patients hospitalized with AHF with in-hospital AKI, exposure to SGLT2i within 10 days post-AKI was associated with decreased mortality and no significant delay in renal recovery.
Abstract 13377: Modulating Mitochondrial Phosphate Transport Shapes Intracellular Ca Signaling to Impact Arrhythmogenesis
Authors: Arpita Deb, Bjorn C Knollmann, Bin Liu
Journal: Circulation (2022)

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced arrhythmic syndrome due to genetic defects of the sarcoplasmic reticulum (SR) Ca release channel complex of ryanodine receptor 2 (RyR2). Our recent study suggests that mitochondria function as a Ca buffer to absorb RyR2-mediated aberrant Ca release and thus mitigate its detrimental consequences in CPVT. Mitochondrial phosphate (Pi) transport has been shown to play a role in both mitochondrial Ca uptake and buffering. Hypothesis: We hypothesize that modulating mitochondrial Pi transport impacts arrhythmogenesis in CPVT by altering mitochondrial Ca uptake and buffering. Methods: Ventricular myocytes were isolated from a genetic CPVT model of CASQ2 knockout (Cnull) mouse. Fluorescent imaging experiments were performed with live cells to examine intracellular Ca dynamics and cellular arrhythmic burden. Mitochondrial Pi transport was modulated by a pharmacological inhibitor or manipulating cytosolic Pi concentration. Results: In the presence of β agonist isoproterenol, an inhibitor of mitochondrial Pi carrier N-ethylmaleimide (NEM) significantly exacerbated Ca handling of intact Cnull cells, resulting in more than 60% of cells displaying pacing-independent Ca oscillations. The NEM treatment also significantly increased the amplitude of cytosolic Ca transient and SR Ca content. Consistent with results obtained in intact cells, NEM treatment exacerbated arrhythmogenic Ca waves and reduced mitochondrial Ca uptake in permeabilized Cnull cells. Moreover, inhibiting mitochondrial Pi transport by lowering cytosolic Pi concentration also increased the frequency of Ca waves and reduced mitochondria Ca uptake in permeabilized Cnull cells. On the contrary, increasing cytosolic Pi concentration reduced the frequency of Ca waves and increased mitochondrial Ca uptake in permeabilized Cnull cells. Conclusions: Modulating mitochondrial Pi transport impacts arrhythmogenesis in CPVT cells through altering mitochondrial Ca uptake and buffering. Enhancing mitochondrial Pi transport may represent a promising therapeutic strategy to reduce arrhythmogenic Ca waves and cardiac arrhythmias in CPVT.
Abstract 12929: Association of Posttraumatic Stress Disorder With Stroke in Women Veterans
Authors: Ramin Ebrahimi, paul dennis, Annie L Shroyer, Carlos Alvarez, jean beckham, Jennifer Sumner
Journal: Circulation (2022)

Introduction: Posttraumatic stress disorder (PTSD) has been associated with ischemic heart disease in women veterans. To date, the evidence for the potential association of PTSD with other cardiovascular disorders remains limited. Furthermore, the overwhelming majority of the research in this area has been conducted predominately in men. The goal of this investigation was to evaluate the association of PTSD with incident stroke in a large cohort of women veterans. Methods: Veterans Affairs (VA) electronic health records were used to identify women veterans aged ≥18 years who visited any VAs nationwide from 1/1/2000-12/31/2017. Diagnosis of each risk factor and disorder was based on administrative billing codes (International Classification of Disease versions 9 and 10). The final study cohorts included 1:2 matched group of patients with and without PTSD respectively. The cohorts were matched for age, traditional risk factors such as diabetes, hypertension, hyperlipidemia and smoking, as well as obesity, chronic kidney disease, psychiatric disorders (depression, anxiety), female specific risk factors (e.g., pre-eclampsia), drug and alcohol dependence, neuroendocrine disorders (e.g., hypo or hyperthyroidism), and number of visits. Cox regression was used to model incident stroke as a function of PTSD. Results: The study population included 398,769 patients, including 132,293 with PTSD and 265,846 matched patients without PTSD. The cox regression analysis revealed that PTSD was significantly associated with greater rates of incident stroke (hazard ratio [HR]=1.64, 95% confidence interval: 1.43-1.86, p&lt;.001). Conclusion: These results point to a strong association of PTSD with incident stroke in women veterans. Further research is indicated to assess the association of PTSD with a broader range of cardiovascular disorders.
Abstract 14198: Implementing an Effective Standardized Bystander Cardiopulmonary Resuscitation Protocol for Golf Courses
Authors: Donald E Casey, Clara Baumgarten
Journal: Circulation (2022)

Introduction: A golf course is the fifth most common public place for cardiac arrest (CA). Currently, no standardized protocol exists for bystander CPR in the event of full CA on a golf course. Informal interviews with golfers and golf course personnel strongly suggest incomplete and variable knowledge about what to do in accordance with most current guidelines. Hypothesis: We hypothesize that development and use of a standardized protocol for the three most critical first steps to assure a person’s survival of an on-golf course CA, including calling 911, initiating high quality bystander CPR with guideline based chest compressions and early defibrillation with a standardized automated external defibrillator (AED) will improve chances of surviving if playing partners, caddies and club staff are well prepared to respond urgently to such an emergency. Methods: We created a four-panel laminated infographic designed to fit easily into every golfer’s bag, assuring a readily available “911-CPR-AED” guide for lay bystanders to initiate chest compressions, notifying the Golf Shop Personnel for getting an AED and any BLS certified persons out to arrest site as fast as possible to deliver defibrillation, and simultaneously readying the golf course grounds crew to meet the arriving rescue ambulance at the front entrance to the course and escorting them quickly and safely out to the CA site. All aspects of this process were shared and approved by leaders of the closest Emergency Medical System (EMS) and hospital emergency department (ED). Results: We simulated with all key stakeholders a full on-course cardiac arrest and 911 call to EMS in accordance with the infographic protocol, including victim resuscitation of a standard CPR mannikin and onsite rescue by paramedics. Bystander CPR was immediately initiated, AED delivered at 3 minutes, ambulance arrival at 6 minutes and full advanced cardiac life support delivered at this time with return of blood pressure. EMS loaded the victim into the ambulance at 12 minutes and was escorted back to the front entrance of the course and then to the local ED. The 911-CPR-AED infographic has now been distributed to all golfers, caddies and staff. Conclusion: An effective, standard bystander CPR protocol now exists for use at any US golf course.
Abstract 12839: Integrated Multi-Omics and Single Nucleus Transcriptomics Highlight Enhanced Adaptive Immune Responses in Human Bicuspid Aortic Valve Stenosis
Authors: Mark C Blaser, Daniel Reichart, Abhijeet Sonawane, Florian Schlotter, Arda Halu, Livia Silva A Passos, Daniel DeLaughter, Wunan Zhou, Ron Blankstein, MARCELO DI CARLI, Maria D Nunes, Tsuyoshi Kaneko, simon robson, Simon C Body, J Daniel D Muehlschlegel, Christine E Seidman, Jonathan G Seidman, Masanori Aikawa, Sasha A Singh, Elena Aikawa
Journal: Circulation (2022)

Introduction: Bicuspid aortic valve (BAV) is the most common congenital cardiac defect, occurring in 1.5% of humans. Due to unknown pathogenic mechanisms, over 70% of those with BAV develop calcific aortic valve disease (CAVD). These patients require valve replacement 25x more frequently and a decade earlier than those with a tricuspid aortic valve (TAV). Objective: Identify cellular and molecular drivers of accelerated disease in BAV-CAVD. Methods: Small RNA-seq, RNA-seq, and proteomics were performed on 70 human aortic valves (11 non-diseased TAVs; fibrotic and calcific stages of 32 TAVs and 27 BAVs excised for CAVD). Single nuclei RNA-seq (snRNA-seq) was completed on 54,608 nuclei from 13 additional human valves (4 non-diseased TAVs; 5 TAVs and 4 BAVs with CAVD). Results: 4,938 miRs, transcripts, and proteins were differentially enriched between stages of BAV- and TAV-CAVD (q&lt;0.05). Multi-omics data, CT-derived valve calcification, and 29 clinical parameters were integrated by latent factor analysis. Protein-protein interaction networks revealed significantly elevated adaptive immune responses in BAV-CAVD: T cell/B cell inflammatory activation was enhanced and SLIT-ROBO signaling disrupted in diseased BAVs. snRNA-seq identified 10 major cell types in human aortic valves: valvular interstitial cells (65% of cells; 3 states), endothelial cells (10%; 2), macrophages (13%), T cells (8%; 2), and B cells (3%; 2). CAVD drove differentiation of dual side-specific endothelial subpopulations, enrichment of CARMN/CACNA1C/ACTA2-high interstitial cells, and substantial immune cell accumulation. B cells were further enriched in BAV- vs. TAV-CAVD. Conclusions: Adaptive immunity underpins molecular differences in BAV- vs. TAV-CAVD and is a novel avenue for tailored pharmacotherapy. We potentiate targeting of key cellular subpopulations by defining the dissociation bias-free transcriptional and cellular diversity of human CAVD at single-cell resolution.
Abstract 14063: Eight Pharmacokinetic-Related Genetic Variants Were Not Associated With Bleeding From Direct Oral Anticoagulants in Non-Valvular Atrial Fibrillation Patients
Authors: Alessandra M Campos-Staffico, Michael P Dorsch, Geoffrey Barnes, Haojie Zhu, Nita Limdi, Jasmine A Luzum
Journal: Circulation (2022)

Background. Atrial fibrillation (AF) is the leading cause of ischemic stroke and treatment has focused on reducing stroke risk through anticoagulation. Direct Oral Anticoagulants (DOACs) are the first-line guideline-recommended therapy in non-valvular AF since they are as effective and safer than warfarin. Although patients bleed less overall from DOACs, bleeding still is the main safety concern with this therapy. Previous studies have shown that genetic variants modify the function of metabolic enzymes or transporters involved in the pharmacokinetics (PK) of DOACs, which then affect DOAC plasma concentrations. However, whether those functional PK genetic variants are significantly associated with the risk of bleeding on DOACs is unknown. Aim. Assess the association of PK-related single nucleotide variants (SNVs) with the risk of bleeding from DOACs in non-valvular AF patients. Methods. A retrospective cohort study was carried out with 2,364 Caucasians with non-valvular AF and treated with rivaroxaban or apixaban. Patients were genotyped as part of the genomic biobank at the University of Michigan Health System. The primary endpoint was a composite of major and clinically relevant non-major (CRNM) bleeding. Cox proportional hazards regression with time-varying analysis assessed the association of 8 SNVs in 5 PK genes ( ABCB1 , ABCG2 , CYP3A4 , CYP3A5 , CYP2J2 ) with the risk of bleeding from DOACs in unadjusted and covariate-adjusted models. Six tests were performed as 3 of the SNVs are in the same haplotype. P-values below the Bonferroni-corrected level of 8.33e-3 were considered statistically significant. Results. A total of 412 (17.4%) major and CRNM bleeding events occurred over 2.27 ± 2.03 years of follow-up. None of the PK SNVs were significantly associated with bleeding risk on DOACs (Table 1). Conclusion. SNVs that affect the function of PK genes were not significantly associated with major and CRNM bleeding from rivaroxaban or apixaban in 2,364 AF patients.
Abstract 13966: The Effect of Diabetes-Associated Adiposomes in Promoting Caveolar Loss and Endothelial Dysfunction
Authors: Imaduddin Mirza, Dina Naquiallah, Chandra Hassan, MArio MAsrur, Francesco M Bianco, Mohamed Ali, Abeer M Mahmoud
Journal: Circulation (2022)

Introduction: Our recent findings revealed that ex vivo cultured human adipose tissues (AT) release extracellular vesicles (adiposomes) that are efficiently captured by endothelial cells. These adiposomes are lipid-enclosed structures that carry bioactive cargos and mediate signaling between the AT and remote cells and tissues. Under hyperglycemia, ceramides could be glycosylated into glycosphingolipids (GSLs), selectively packed in adiposomes to be cleared away from adipocytes. Hypothesis: We hypothesize that the AT from obese, diabetic patients (OB-T2D) creates excess GSL-rich adiposomes, which are incorporated into endothelial cells causing alterations in endothelial cell properties and function. Methods: AT samples were collected from OB-T2D and non-OB subjects (n=10, each). Nanoparticle tracking and electron microscopy were used to analyze and visualize these adiposomes, and mass spectrometry was used to study their content. Adiposome uptake, lipid fusion, and changes in endothelial membrane structure and signaling pathways were also assessed. Results: Compared to non-obese controls, adiposomes isolated from OB-T2D were higher in number and contained higher levels of GSLs. When added to cultured endothelial cells, GSL-rich adiposomes tended to accumulate in an endothelial structure known as caveolae, which concentrate signaling molecules such as endothelial nitric oxide synthase (eNOS) and others. Electron microscopy showed a caveolar loss from the cell surface, and live TIRF microscopy indicated increased caveolar detachment. We observed induced phosphorylation of the key caveolar protein, caveolin-1, by GSL-rich adiposomes known to cause caveolar fission. This effect was mediated via activation of Src kinase (induced phosphorylation), as it was inhibited by the Src kinase inhibitor, PP2. These molecular events were accompanied by reductions in endothelial nitric oxide synthase (eNOS) activation and nitric oxide production, disturbances in endothelial gap junction, and increased permeability. Conclusion: we conclude that dysfunctional AT in OB-T2D produces GSL-loaded adiposomes that fuse with endothelial cells and activate the Src kinase pathway resulting in caveolar fission and endothelial cell dysfunction
Abstract 14155: Concomitant Use of Creatine Kinase MB and High-Sensitivity Troponin: What is the Cost?
Authors: Joshua Mills, Hoi-Ying Yu, Erin Van Enkevort, Samantha Hoffman, Martin Matsumura, Stephen J Voyce
Journal: Circulation (2022)

Introduction: AHA/ACC guidelines recommend the use of serial high sensitivity troponin (hs-Tn) assays to assess for cardiac injury 1 and addition of CK-MB adds no benefit. However, in the clinical setting, CK-MB assays continues to be ordered concomitantly with hs-Tn in evaluation of suspected myocardial injury/infarction. We performed this study to determine whether the addition of CK-MB to hs-Tn alters diagnostic or therapeutic decisions and to determine its effect on patient outcomes. The financial aspects of this practice were also analyzed Methods: We performed a retrospective review of patients in the Geisinger Health care system from 2018 through 2021. Those having both a CK-MB and a hs-Tn drawn within 24 hours were included. Test results were categorized as concordant or discordant. Patient demographics, clinical profiles, medications and rates of diagnostic cardiac catheterization and subsequent PCI and primary admission and discharge diagnosis were collected from the EMR and analyzed. We used Medicare reimbursement data for estimates of financial impact. Results: A total of 18,727 unique patients had a CK-MB and hs-Tn performed within a 24-hour window. Of these, 49.1% (9,149) had concordant values and 50.9% (9,533) had discordant values. Of those with discordant results, 8,801 (92.3%) patients had abnormal hs-Tn result but normal CK-MB. Abnormal CK-MB with a normal hs-Tn was resulted in 840 patients (8.8%). There was a total of 42,276 CK-MB determinations during our study timeframe which averages out to 2.3 CK-MB/patient. Medicare reimbursement for CKMB is $11.55. Conclusions: This 3-year study demonstrates clinicians still frequently ordered CKMB in patients with concomitant hs-Tn determinations and 49.1%% results are concordant with hs-Tn results yielding no additional clinical information versus use of hs-Tn alone. The cost of this practice is estimated at $239,749.31 for the study period. Data on patients with discordant results and impact on decision process and cost is under analysis and will be available for presentation.
Abstract 13331: Low Statin Adherence Identified Across Diverse Populations in the All of Us Research Program
Authors: Gabriela V Escobar, Anne A de Hond, Ashish Sarraju, Fatima Rodriguez, Tina Hernandez-Boussard
Journal: Circulation (2022)

Introduction: Statins are a cornerstone of primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD), the leading cause of death in the US. Despite conclusive evidence to the efficacy and safety of statins, low adherence remains a public health challenge. Although patient, clinician, and health system barriers to statin adherence have been documented, the effect of national policies targeting prescription access remains largely understudied. This study sought to assess the effect of the 2016 US Preventive Services Task Force (USPSTF) recommendation of statins on racial/ethnic disparities in treatment adherence. Methods: Utilizing records of the novel All of Us Research Program, a dataset of historically underrepresented groups in health research, we compared statin use in adult ASCVD non-Hispanic White (NHW) patients before (2014-2016) and after (2017-2020) the USPSTF recommendation with Black and Hispanic patients. Statin use was measured as percent days covered (PDC). Trends were compared using a regression model with demographics and an indicator variable for the change in recommendation as covariates. Regression coefficients and p-values were analyzed to assess the effect of the policy. Results: The study included 94,883 unique statin prescription records belonging to a patient cohort of which 52% were female, 21% Black and 12% Hispanic, with a mean age of 61.93 years. There was poor statin adherence across all racial/ethinic subgroups (PDC &lt; 0.80). Following the policy, PDC increased 3.1% overall (p&lt;0.01), 12 percentage points in Black patients and no change in Hispanics with respect to NHW. Conclusion: Our results provide preliminary evidence that the 2016 USPSTF changes increased statin adherence, yet there were differential effects among racial/ethnic subgroups. To address population adherence disparities, more research is needed to inform policy that will facilitate access for underserved populations in the United States.